Serial SOFA‐score trends in ICU‐admitted COVID‐19 patients as predictor of 28‐day mortality: A prospective cohort study

Abstract Background and Aim The efficacy of Sequential Organ Failure Assessment (SOFA) score as predictor of clinical outcomes among ICU‐admitted COVID‐19 patients is still controversial. We aimed to assess whether SOFA‐score in different time intervals could predict 28‐day mortality compared with other well‐acknowledged risk factors of COVID‐19 mortality. Methods This observational prospective cohort was conducted on 1057 patients from March 2020 to March 2022 at Masih Daneshvari Hospital, Iran. The univariate and multivariate Cox proportional analysis were performed to assess the hazards of SOFA‐score models. Receiver operating characteristic (ROC) curves were designed to estimate the predictive values. Results Mean SOFA‐score during first 96 h (HR: 3.82 [CI: 2.75–5.31]), highest SOFA‐score (HR: 2.70 [CI: 1.93–3.78]), and initial SOFA‐score (HR: 1.65 [CI: 1.30–2.11]) had strongest association with 28‐day mortality (p < .0001). In contrast, SOFA scores at 48 and 96 h as well as Δ‐SOFA: 48‐0 h and Δ‐SOFA: 96‐0 h did not show significant correlations. Among them, merely mean SOFA‐score (HR: 2.28 [CI: 2.21–3.51]; p < .001) remained as independent prognosticator on multivariate regression analysis; though having less odds of predicting value compared with age (HR: 3.81 [CI: 1.98–5.21]), hypertension (HR: 3.11 [CI: 1.26–3.81]), coronary artery disease [CAD] (HR: 2.82 [CI: 1.51–4.8]), and diabetes mellitus (HR: 2.45 [CI: 1.36–2.99]). The area under ROC (AUROC) for mean SOFA‐score (0.77) and highest SOFA‐score (0.71) were larger than other SOFA intervals. Calculating the first 96 h of SOFA trends, it was obtained that fatality rate was <12.3% if the score dropped, between 28.8% and 46.29% if the score remained unchanged, and >50.45% if the score increased. Conclusion To predict the 28‐day mortality among ICU‐admitted COVID‐19 patients, mean SOFA upon first 96 h of ICU stay is reliable; while having inadequate accuracy comparing with well‐acknowledged COVID‐19 mortality predictors (age, diabetes mellitus, hypertension, CAD). Notably, increased SOFA levels in the course of first 96 h of ICU‐admission, prognosticate at least 50% fatality regardless of initial SOFA score.

of first 96 h of ICU-admission, prognosticate at least 50% fatality regardless of initial SOFA score.  19) worldwide until the end of July 2022 1 ; and it is estimated that 5%-35% of these had experienced to be admitted for at least 1 day in intensive care units (ICUs). 2 The most common complications causing COVID-19 patients to be hospitalized include acute respiratory distress syndrome (ARDS), 3 acute kidney failure, 4,5 thromboembolic and cardiac events, 6,7 elevated inflammation conditions, 8 and liver injuries. 9 While the severity of COVID-19 has been started to depreciate by the improvements in the rate of vaccination, the capacity of ICUs could be mostly occupied by COVID-19 patients 10 ; particularly in countries with a slower pace of vaccination, causing them to face consecutive waves of SARS-CoV-2 infection. 8 This issue has created concerns about the capacity of ICUs providing clinical support for patients during the further potential infection waves. This may necessitate health officials to identify patients with lower chance of surviving and to prioritize those requiring to receive mechanical ventilation and other advanced therapeutic options as well. 11,12 Accordingly, a survey on the comparison of ventilator triage policies among hospitals in the United States, discovered 26 different triage strategies for COVID-19 pneumonia that 20 of them had utilized Sequential Organ Failure Assessment (SOFA) scoring system models. 13 SOFA score as an evaluator of organ failure and severity of the disease, was first introduced in 1996 and its functionality has been on the basis of examining the six key organs' functional status: coagulation function, central nervous system, kidney, liver, respiration, and circulation 14,15 (Supporting Information: Table 1). Although this scoring system was developed to qualify organ failure and not for predicting outcomes, a clear link between mortality and organ dysfunction has been established. 16 Moreover, some data have supported the accuracy of SOFA score for evaluating the severity and 60-day mortality of SARS-CoV2 infected individuals. 17 However, the hypothesis has remained controversial that the SOFA score has lower accuracy in cases with COVID-19 pneumonia, albeit an independent risk factor of mortality. That's due to the fact that these individuals are more likely to have significant single-organ failure and less variability in their SOFA scores. Therefore, we found interest in assessing whether measuring the series of recorded SOFA score alterations could help us refine the clinical outcome of COVID-19, while being considered an accurate prognostic factor among ICU- Masih Daneshvari Hospital was considered as one of the main tertiary patient referral centers during the COVID-19 pandemic with the remarkable capacity of patient admission (ICU-beds = 800).
All the cases were verified by real-time-polymerase chain reaction, and their hospital admission and management were carried out based on the protocols defined by the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) of Iran. 18 The indications for ICU admission were based on the presence of each of the (1).
Respiratory failure which needs invasive/noninvasive ventilation, or (2). Septic shock which needs any dosage of vasopressors; in fact, septic shock is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. So the patients with septic shock could be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mmHg or greater, and the serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. 19 Moreover, it is worth mentioning that for conducting the current study, the recommendations put forward in the "Guidelines for reporting of statistics for clinical research in urology" were all reviewed and followed for guidance on the proper analysis, reporting, and interpretation of clinical research. 20 Also, the methodology of this study was checked and revisited based on the STROBE guidelines. 21

| Inclusion and exclusion criteria of the patients
The inclusion criteria of this study were as follows; COVID-19 patients who were admitted in ICU settings during the first 6 h of referral to emergency department. Based on NIRTLD protocols, all the patients received intravenous methylprednisolone, and additionally, some received Remdesivir with similar standard dosages (methylprednisolone as 1000 mg/day pulse therapy in first 3 days followed by 1 mg/kg in every 12 h for next 10 days, and Remdesivir with loading dosage of 200 mg in 1st day and 100 mg dosage in the next 5 days). Patients who did not undergo the mentioned drugs or received different doses adjusted due to their clinical conditions (such as uncontrolled diabetes or sever renal failure) were excluded from the study. Further, those who were clinically selected to receive anti-interleukin-6 (Tocilizumab), Baricitinib, or extracorporeal membrane oxygenation were excluded. Overall, 1057 cases were enrolled in this study. Since this was a prospective cohort, at the end-point of the study, it was established that patients could all fell into either two groups based on their 28-day mortality status during ICU admission (765 patients as survived vs. 292 patients as nonsurvived). They had their daily SOFA scores calculated at 5 a.m. morning from ICU admission until discharge/death consecutively. SOFA score was calculated by the skilled emergency medicine, anesthesiology, or internal medicine residents using online medical software "MDCalc" previously authorized for severity scores calculations. 22 Other data considering demographic, comorbidities, clinical and laboratory characteristics as well as received therapeutics were also compiled.

| Data collection
All the mentioned data were prospectively gathered using online collection system forms specifically designed for the hospital research studies. For enhancing the reliability, the data collection process was reassessed by two medical researchers (F. E. T. and F. S. R.) individually and the extracted data were double-checked.

| Definitions
In our assessment, "initial SOFA score" was defined as the SOFA score upon ICU admission; "SOFA score at 48 h" and "SOFA score at 96 h" were defined as SOFA score at 48 and 96 h after ICU admission, respectively; "Δ-SOFA: 48-0 h" was considered the subtraction of upon-hospitalization SOFA score from 48-h SOFA score; and "Δ-SOFA: 96-0 h" was determined as the subtraction of upon-hospitalization SOFA score from 96-h SOFA score. "Mean SOFA score" was deemed as the average score of SOFA calculated in the first 4 days of ICU admission.

| Statistical analysis
All data were evaluated in terms of being normally disturbed using Shapiro-Wilk test. Continuous and categorical data have been described respectively as mean ± standard deviation and n (% to compare with SOFA score trends. The selection of mentioned comorbidities was based on the clinical importance of variables found in recent research 23,24 as well as data availability of our study. We also designed receiver operating characteristic (ROC) curve for different statuses of the SOFA scores to more effectively represent the predictability of each variable. Two-sided α < ·05 was deemed as the statistical significance. The statistics were all conducted by the IBM SPSS statistics (version: 26.0).

| Baseline characteristics
All 1057 enrolled patients were split into two groups; the first group entails a total of 765 patients who had survived at least 28 days after study. And the second group is made up of a total of 292 patients who had not survived the first 28 days after study onset. Table 1 shows the initial baseline characteristics of patients divided by study groups. Age as the main demographic feature had a median of 71 years in the survived group, and 74 years in the nonsurvived group; marking a statistically remarkable difference between the two groups (p < .001). The sex ratio of cases differed between two groups. Male patients formed 78.3% and 88.0% of the survived group and nonsurvived group, respectively; highlighting that male gender was of statistically significant abundance in the nonsurvived group (p < .001). The mean BMI was also recorded to be prominently higher in the nonsurvived group, compared with the survived group ( 3.2 | SOFA score trends as 28-day mortality predictor In respectively. These all had a stronger correlation to 28-day mortality compared with mean, highest, and initial SOFA scores. Supporting Information: Figure 1 depicts the ROC curves drawn for eight of the main indices with potential diagnostic roles. The area under the curve (AUC) for each of these eight indices, is a measure of the ability of that classifier to make a distinction. On that account, the higher the AUC gets, the better the diagnostic performance of that index would be.
Accordingly, as it is displayed in this figure, our findings showed that the diagnostic factor with the highest AUC is age, therefore it has the best diagnostic ability among all evaluated factors.  were not admitted to ICU settings, which therefore could be potentially associated to better survival. And fourth, we had a relatively large study population (1057 patients) and we conducted this study prospectively; compared with retrospective studies previously performed. 16 Until now, no high-yield systematic review analysis has been reported on the SOFA score's trends accuracy and its predictive ability in detecting COVID-19 severity. This scoring system was developed to quantify organ failure degrees in patients with severe sepsis, and it has been since well-established for use in ICU patients globally. 29  SBMU.1399049). We declare that the supporting source/financial relationships had no involvement in study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.

CONFLICTS OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are all available for interested readers on request from the corresponding author.

TRANSPARENCY STATEMENT
The lead author Atefeh Abedini affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.